Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common, serious side effects that can lead to dose reductions or early discontinuation of chemotherapy, reducing the efficacy of cancer treatments. It can cause debilitating symptoms and also significantly impacts the patient's quality of life. An estimated 30 to 40 percent of cancer patients treated with chemotherapy experience CIPN.
The peripheral nervous system (PNS) consists of sensory neurons running from stimulus receptors that inform the central nervous system (CNS) of the stimuli, and motor neurons running from the spinal cord to the effectors that take action. In CIPN, an anticancer drug could impair both sensory and motor functions. The symptoms usually start in the hands and/or feet and creep up the arms and legs. Sometimes it feels like a tingling or numbness. Other times, it's more of a shooting and/or burning pain or sensitivity to temperature. It can include sharp, stabbing pain. CIPN can also lead to hearing loss, blurred vision and change in taste. CIPN can make it difficult to perform normal day-to-day tasks like buttoning a shirt, sorting coins in a purse, or walking. In addition, the motor neuron dysfunction manifest as cramps, difficulty with fine motor activities (e.g. writing or dialing a phone), gait disturbances, paralysis, spasms, tremors and weakness.
CIPN may result from the use of numerous chemotherapeutic agents, including, but limited to, Ixabepilone (Ixempra Kit), arsenic trioxide (Trisenox), cytarabine (Cytosar-U, Depocyt, generics), etoposide, hexamethylmelamine (altretamine [Hexalen]), Ifosfamide (Ifex, generics), methotrexate (Trexall, generics), procarbazine (Matulane) and vinblastine. The chemotherapeutic drugs that most commonly elicit CIPN include platinum compounds (cisplatin, carboplatin, oxaliplatin), vincristine, taxanes (docetaxel, paclitaxel), epothilones (ixabepilone), bortezomib (Velcade), thalidomide (Thalomid) and lenalidomide.
For treating the pain associated with CIPN, agents that appear promising include the antidepressants duloxetine and venlafaxine, which are both serotonin/norepinephrine-reuptake inhibitors. Another promising agent is a topical compound of the muscle-relaxant baclofen, the antidepressant amitriptyline, and the analgesic ketamine Outside of clinical trials, CIPN symptoms are commonly managed in a manner similar to other types of nerve pain—that is, with a combination of physical therapy, complementary therapies such as massage and acupuncture, and medications that can include steroids, antidepressants, anti-epileptic drugs, and opioids for severe pain. But these therapies have not demonstrated true efficacy for CIPN, and virtually all of the drugs to treat peripheral neuropathy carry side effects of their own.
The actual causes of CIPN, on the cellular and tissue level, is still largely a matter of speculation. Oxidative stress may play a key role in CIPN. It was found that antioxidant machinery (e.g. plasma glutathione (GSH) and α- and γ-tocopherol concentrations) of cancer patents with chemotherapy decreased and the GSH redox state became more oxidized. In a rat model of painful oxaliplatin-induced neuropathy, oxidative stress was found to be an important component that mediates pain. In the plasma of oxaliplatin-treated rats, the increases of carbonylated protein and thiobarbituric acid reactive substances in the sciatic nerve and the spinal cord indicated the resultant protein oxidation and lipoperoxidation in these locations, respectively. Oxidative imbalance manifests itself as a mediator of inflammatory pain as well. Use of the anticancer drug cisplatin results in severe cell death of sensory neurons derived from dorsal root ganglia following increase in oxidative stress. Oxidative stress is also found to impair the autonomic nervous system and manifests itself in symptoms such as hearing loss. The results from antioxidants also support a key role of oxidative stress in mediating CIPN. The antineuropathic effect of antioxidant silibinin or α-tocopherol shows as about 50% oxaliplatin-induced behavioral alterations. Administration of anticancer drug bortezomib or oxaliplatin, which elicits TRPA1-dependent hypersensitivity, produced a rapid, transient increase in plasma of carboxy-methyllysine, a by-product of oxidative stress. Short-term systemic treatment with either HC-030031 or α-lipoic acid (an antioxidant) could completely prevent hypersensitivity if administered before the cytotoxic drug. The findings highlight a key role for early activation/sensitization of TRPA1 by oxidative stress by-products in producing CIPN. For preventing the onset of CIPN, further clinical testing of many antioxidative stress agents, such as glutathione, acetyl-L-carnitine and alpha-lipoic acid has been suggested.
Another mechanism underlying CIPN is excitotoxicity where increased release of glutamate forces N-methyl D-aspartate (NMDA) receptors to remain open, allowing increased calcium flux into neurons, resulting in overexcitation and eventually neuronal rupture. The end result of this process is pain without a painful stimulus, also known as neuropathic pain. N-Acetyl-aspartyl-glutamate (NAAG) is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into N-Acetyl-aspartyl (NAA) and glutamate. Glutamate carboxypeptidase inhibition could reduce the severity of chemotherapy-induced peripheral neurotoxicity in rat.
As there are no proven treatments, there is a need for methods to properly treat chemotherapy-induced peripheral neuropathy. The present invention provides just such a method.